CN110627786A - Preparation method of tadalafil intermediate - Google Patents
Preparation method of tadalafil intermediate Download PDFInfo
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- CN110627786A CN110627786A CN201911038552.0A CN201911038552A CN110627786A CN 110627786 A CN110627786 A CN 110627786A CN 201911038552 A CN201911038552 A CN 201911038552A CN 110627786 A CN110627786 A CN 110627786A
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- methyl ester
- tadalafil
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of a tadalafil intermediate. According to the method, the high-purity tadalafil intermediate can be prepared in a high yield under the conditions of a certain reagent proportion and reaction temperature by taking the easily-obtained piperic acid acyl chloride and the like as raw materials, the whole synthesis process can be regarded as one-step reaction, compared with the prior art, the complex reaction steps are obviously reduced, the reaction conditions are mild, the operation is simple, and the method can be applied to large-scale industrial production of tadalafil.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis. More particularly, relates to a preparation method of a tadalafil intermediate.
Background
Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5(PDE5) and is approved by the FDA for marketing in the united states as a drug for the treatment of Male Erectile Dysfunction (MED) in 2003. Recent clinical research shows that tadalafil can also be used for treating pulmonary hypertension, and has wide application prospect. Compared with similar medicines of sildenafil or vardenafil, tadalafil has the advantages of high activity, quick response, long drug effect, small side effect and the like, and is a hot spot of research and development.
At present, the prior art mainly uses D-tryptophan methyl ester, D-tryptophan methyl ester hydrochloride, D-tryptophan and NαReacting Boc-D-tryptophan serving as a raw material with piperonal or analogues thereof, and preparing tadalafil through a series of synthetic steps. The above synthetic routes all require multiple reactions, producing a variety of different intermediates simultaneously. The intermediate 1 is one of a plurality of intermediates in the preparation process of tadalafil, and can be prepared by reacting D-tryptophan methyl ester with piperonal:
however, the piperonal adopted by the method is not easy to obtain as a tubular medicament, and is not beneficial to large-scale production.
To solve the above starting material problems, Wupuhua et al disclose another synthetic route to the intermediate 1:
in the synthetic route, D-tryptophan methyl ester hydrochloride is condensed with piperic acid acyl chloride to prepare a compound 9, a compound 10 is prepared by the action of a Lawson reagent, and finally a compound 7 (an intermediate 1) is prepared by the reflux of methyl iodide and the reduction and cyclization of sodium borohydride, wherein the yield is 62.5% (Wupul, Xieypeng. tadalafil synthetic route scheme [ J ]. Chinese journal of pharmaceutical chemistry 2015,25(05): 407-. Although the method avoids using a tubular raw material piperonal, the method has the defects of multiple steps, easy generation of various byproducts, low yield, reaction at-78 ℃ in the last step, and unpleasant smell of a Lawson reagent used in the reaction process, and is not suitable for actual production.
Therefore, a tadalafil intermediate preparation method which avoids the use of controlled reagents, has simple steps, mild reaction conditions, high yield and good purity is urgently needed.
Disclosure of Invention
The invention aims to solve the technical problems of overcoming the defects and shortcomings of complicated steps, harsh reaction conditions and the like of a conventional reaction in the prior art, and provides a tadalafil intermediate preparation method which avoids the use of a tubular reagent, has simple steps, mild reaction conditions, high yield and good purity.
The above purpose of the invention is realized by the following technical scheme:
a preparation method of a tadalafil intermediate comprises the following reaction route:
the method specifically comprises the following steps:
dissolving D-tryptophan methyl ester hydrochloride and piperic acid acyl chloride in an aprotic organic solvent, adding trifluoroacetic acid, stirring and reacting for 8-12 h at 30-45 ℃ under the protection of nitrogen, adding sodium triacetoxyborohydride, continuing to react for 2-4 h, performing post-treatment, and separating to obtain an intermediate 1;
wherein the mass ratio of the D-tryptophan methyl ester hydrochloride to the trifluoroacetic acid is 1 (0.02-0.5).
The mechanism of the above reaction may be:
firstly, carrying out Friedel-crafts acylation reaction on D-tryptophan methyl ester hydrochloride and piperic acid acyl chloride under the action of a trace acid catalyst trifluoroacetic acid, then carrying out Schiff base reaction, and adding sodium triacetoxyborohydride for further reductive amination to form an intermediate 1, wherein the imine compound is unstable. The whole reaction process is completed in one step, no intermediate product needs to be separated, the reaction process is controlled by adding sodium triacetoxyborohydride, and the intermediate 1 can be prepared by one-step reaction.
Lewis acid (such as aluminum trichloride) is usually adopted for catalysis in the Friedel-crafts acylation reaction, but the catalysts are easy to generate hydroxide colloid in the reaction process, can cover the surface of reactants to influence the reaction process, and are easy to block filter paper and difficult to filter; moreover, in order to ensure the normal running of the friedel-crafts-acylation reaction, a large amount of metal halide is generally added, which is relatively high in cost. The applicant surprisingly found in practice that a catalytic amount of protonic acid trifluoroacetic acid is adopted, and a Friedel-crafts reaction and a Schiff base reaction can be simultaneously catalyzed without adding other reagents, the protonic acid trifluoroacetic acid can react to form an imine compound within a certain time, and an intermediate 1 obtained after reduction has high yield and purity and accords with the idea of green chemistry.
Preferably, the mass ratio of the D-tryptophan methyl ester hydrochloride to the trifluoroacetic acid is 1 (0.05-0.2).
More preferably, the mass ratio of D-tryptophan methyl ester hydrochloride to trifluoroacetic acid is 1: 0.05. Applicants found in practice that the yield of intermediate 1 was higher when the mass ratio of D-tryptophan methyl ester hydrochloride to trifluoroacetic acid was 1: 0.05.
Preferably, the reaction temperature is 30-40 ℃.
More preferably, the temperature of the reaction is 30 ℃. The applicant found in practice that the yield of intermediate 1 was higher when the temperature of the reaction was 30 ℃.
Furthermore, the mass ratio of the D-tryptophan methyl ester hydrochloride to the sodium triacetoxyborohydride is 1 (1-5).
Preferably, the mass ratio of the D-tryptophan methyl ester hydrochloride to the sodium triacetoxyborohydride is 1 (3-5).
More preferably, the mass ratio of D-tryptophan methyl ester hydrochloride to sodium triacetoxyborohydride is 1: 3.
Further, the aprotic organic solvent is selected from one of tetrahydrofuran, toluene, dichloromethane, N dimethylformamide, acetonitrile and dimethylsulfoxide.
Preferably, the aprotic organic solvent is tetrahydrofuran.
The invention has the following beneficial effects:
according to the preparation method of the tadalafil intermediate, the tadalafil intermediate with high purity can be prepared in a high yield by taking the piperic acid acyl chloride and the like which are easily obtained as raw materials under the conditions of a certain reagent proportion and reaction temperature, and the whole synthesis process can be regarded as one-step reaction.
Drawings
Fig. 1 is a synthesis scheme of the tadalafil intermediate preparation method of the present invention.
Fig. 2 is a hydrogen spectrum of tadalafil intermediate prepared in example 1 of the present invention.
Fig. 3 is a mass spectrum of tadalafil intermediate prepared in example 1 of the present invention.
Fig. 4 is a high performance liquid chromatogram of the tadalafil intermediate prepared in example 1 of the present invention.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
The synthetic route of the preparation method of the tadalafil intermediate is as follows:
example 1 preparation of Tadalafil intermediate
The tadalafil intermediate is prepared and isolated by the following method:
s1, dissolving 9.34g D-tryptophan methyl ester hydrochloride and 8.12g piperic acid acyl chloride in 300mL redistilled tetrahydrofuran, adding 0.14mL trifluoroacetic acid, stirring and reacting at 30 ℃ for 10H under the protection of nitrogen, adding 23.30g sodium triacetoxyborohydride, continuing to react for 3H, after the reaction is monitored by a TLC plate, concentrating the reaction solution to about 10mL, adding 200mL deionized water, extracting twice by using 200mL ethyl acetate, combining organic phases, washing twice by using 150mL saturated sodium chloride, drying under reduced pressure to obtain 12.33g of intermediate 1, wherein the yield is 86.95%, the purity is 98.76%, and ESI (M/z) [ M-HCl + H ] (M-HCl + H)]+：351.1334。
Example 2 influence of trifluoroacetic acid addition, temperature, solvent on intermediate 1 yield
Reference example 1 preparation of tadalafil except that intermediate 1 was prepared using different amounts of trifluoroacetic acid added, temperatures, solvents and the yield of the resulting intermediate 1 was calculated. Specific trifluoroacetic acid addition, temperature, solvent and experimental results are shown in table 1.
TABLE 1 influence of trifluoroacetic acid addition, temperature, solvent on intermediate 1 yield
As can be seen from table 1:
(1) under the same conditions of reaction temperature and solvent, when the mass ratio of D-tryptophan methyl ester hydrochloride to trifluoroacetic acid is 1 (0.05-0.2), the yield of the intermediate 1 is over 75%, the yield is higher, and when the yield is beyond the range, the yield of the intermediate 1 is remarkably reduced to below 50%;
(2) under the condition that the quantity ratio of substances and the reagent are the same, the yield of the prepared intermediate 1 is reduced along with the rise of the reaction temperature, wherein when the reaction temperature is 30-40 ℃, the yield can reach more than 70%;
(3) under the condition of the same quantity ratio and temperature of the substances, different solvents are selected to influence the yield of the intermediate 1, wherein the yield is the highest when the solvent is tetrahydrofuran.
Experimental example 1 detection of Tadalafil intermediate by Hydrogen Spectroscopy, Mass Spectroscopy and high Performance liquid chromatography
And (3) carrying out hydrogen spectrum, mass spectrum and high performance liquid chromatography detection on the tadalafil intermediate prepared in the example 1 to obtain a graph 2-4.
The detection method of the high performance liquid chromatography comprises the following steps:
an appropriate amount of the tadalafil intermediate prepared in example 1 was precisely weighed, and according to 0512 high performance liquid chromatography in the fourth general rule of the pharmacopoeia of China (2015 edition), octadecylsilane chemically bonded silica was used as a filler, the detection wavelength was set to 285nm, the flow rate was set to 1.0ml/min, the sample amount was 10 μ l, 0.1% trifluoroacetic acid was used as a mobile phase A, acetonitrile was used as a mobile phase B, gradient elution was performed according to the conditions in Table 2, and the chromatogram was recorded.
TABLE 2 high performance liquid chromatography gradient elution conditions
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 5 | 80 | 20 |
| 20 | 70 | 30 |
| 30 | 70 | 30 |
| 33 | 10 | 90 |
| 45 | 10 | 90 |
As can be seen from FIG. 4, the time to peak of the tadalafil intermediate was 14.802 min.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A preparation method of a tadalafil intermediate is characterized by comprising the following reaction route:
the method specifically comprises the following steps:
dissolving D-tryptophan methyl ester hydrochloride and piperic acid acyl chloride in an aprotic organic solvent, adding trifluoroacetic acid, stirring and reacting for 8-12 h at 30-45 ℃ under the protection of nitrogen, adding sodium triacetoxyborohydride, continuing to react for 2-4 h, performing post-treatment, and separating to obtain an intermediate 1;
wherein the mass ratio of the D-tryptophan methyl ester hydrochloride to the trifluoroacetic acid is 1 (0.02-0.5).
2. The method according to claim 1, wherein the mass ratio of D-tryptophan methyl ester hydrochloride to trifluoroacetic acid is 1 (0.05 to 0.2).
3. The method according to claim 2, wherein the mass ratio of D-tryptophan methyl ester hydrochloride to trifluoroacetic acid is 1: 0.05.
4. The method according to claim 1, wherein the reaction temperature is 30 to 40 ℃.
5. The method according to claim 4, wherein the reaction temperature is 30 ℃.
6. The preparation method according to claim 1, wherein the mass ratio of the D-tryptophan methyl ester hydrochloride to the sodium triacetoxyborohydride is 1 (1-5).
7. The preparation method according to claim 6, wherein the mass ratio of the D-tryptophan methyl ester hydrochloride to the sodium triacetoxyborohydride is 1 (3-5).
8. The method according to claim 7, wherein the mass ratio of D-tryptophan methyl ester hydrochloride to sodium triacetoxyborohydride is 1: 3.
9. The method according to claim 1, wherein the aprotic organic solvent is one selected from tetrahydrofuran, toluene, dichloromethane, N-dimethylformamide, acetonitrile and dimethylsulfoxide.
10. The method according to claim 9, wherein the aprotic organic solvent is tetrahydrofuran.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554108A (en) * | 2013-10-29 | 2014-02-05 | 安徽万邦医药科技有限公司 | Improved tadalafil preparation method |
| CN103772384A (en) * | 2014-01-23 | 2014-05-07 | 苏州大学 | Preparation method of tadalafil |
| CN106432235A (en) * | 2016-10-19 | 2017-02-22 | 南通大学 | Beta-carboline derivative targeted to CDK and DNA and preparation method and medical application thereof |
| CN106977516A (en) * | 2017-03-02 | 2017-07-25 | 山东裕欣药业有限公司 | A kind of preparation method of Tadalafei |
| US20190263802A1 (en) * | 2018-02-28 | 2019-08-29 | Ferro Therapeutics, Inc. | Compounds and method of use |
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- 2019-10-29 CN CN201911038552.0A patent/CN110627786B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554108A (en) * | 2013-10-29 | 2014-02-05 | 安徽万邦医药科技有限公司 | Improved tadalafil preparation method |
| CN103772384A (en) * | 2014-01-23 | 2014-05-07 | 苏州大学 | Preparation method of tadalafil |
| CN106432235A (en) * | 2016-10-19 | 2017-02-22 | 南通大学 | Beta-carboline derivative targeted to CDK and DNA and preparation method and medical application thereof |
| CN106977516A (en) * | 2017-03-02 | 2017-07-25 | 山东裕欣药业有限公司 | A kind of preparation method of Tadalafei |
| US20190263802A1 (en) * | 2018-02-28 | 2019-08-29 | Ferro Therapeutics, Inc. | Compounds and method of use |
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